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Protein

Methylmalonic aciduria and homocystinuria type D protein, mitochondrial

Gene

MMADHC

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Involved in cobalamin metabolism (PubMed:18385497, PubMed:23415655, PubMed:24722857, PubMed:26364851). Plays a role in regulating the biosynthesis of two coenzymes, methylcobalamin and adenosylcobalamin (PubMed:18385497, PubMed:24722857). Plays a role in regulating the proportion of methylcobalamin and adenosylcobalamin (PubMed:23415655, PubMed:24722857). Promotes oxidation of cob(II)alamin bound to MMACHC (PubMed:26364851).4 Publications

GO - Biological processi

  • cobalamin metabolic process Source: UniProtKB
  • coenzyme biosynthetic process Source: UniProtKB
Complete GO annotation...

Enzyme and pathway databases

ReactomeiR-HSA-196741. Cobalamin (Cbl, vitamin B12) transport and metabolism.
R-HSA-3359473. Defective MMADHC causes methylmalonic aciduria and homocystinuria type cblD.

Names & Taxonomyi

Protein namesi
Recommended name:
Methylmalonic aciduria and homocystinuria type D protein, mitochondrial
Alternative name(s):
CblD3 Publications
Gene namesi
Name:MMADHC
Synonyms:C2orf25, CL25022
ORF Names:HSPC161, My011
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

HGNCiHGNC:25221. MMADHC.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: Reactome
  • mitochondrion Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Mitochondrion

Pathology & Biotechi

Involvement in diseasei

Methylmalonic aciduria and homocystinuria type cblD (MMAHCD)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Clinical features include developmental delay, hyotonia, mental retardation, seizures, megaloblastic anemia. Some patients manifest combined methylmalonic aciduria and homocystinuria (referred to as cblD original), some have only isolated homocystinuria (cblD variant 1), and others have only methylmalonic aciduria (cblD variant 2).
See also OMIM:277410
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_043843108S → SLAEPLS in MMAHCD; cblD variant 2. 1
Natural variantiVAR_043844182T → N in MMAHCD; cblD variant 1; impairs interaction with MMACHC. 3 PublicationsCorresponds to variant rs118204045dbSNPEnsembl.1
Natural variantiVAR_043845204 – 232Missing in MMAHCD; cblD original. 1 PublicationAdd BLAST29
Natural variantiVAR_043846249Y → C in MMAHCD; cblD variant 1. 1 PublicationCorresponds to variant rs118204046dbSNPEnsembl.1
Natural variantiVAR_043847259L → P in MMAHCD; cblD variant 1; decreases methylcobalamin levels and increases adenosylcobalamin levels; no effect on interaction with MMACHC. 3 PublicationsCorresponds to variant rs118204044dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi165F → A: Mildly decreases methylcobalamin levels and strongly increases adenosylcobalamin levels. 1 Publication1
Mutagenesisi186M → A: Decreases methylcobalamin levels. No effect on interaction with MMACHC. 2 Publications1
Mutagenesisi189W → A: Decreases methylcobalamin levels. Impairs interaction with MMACHC. 2 Publications1
Mutagenesisi197R → A: Decreases methylcobalamin levels, but increases adenosylcobalamin levels. 1 Publication1
Mutagenesisi204F → A: Decreases methylcobalamin levels and mildly increases adenosylcobalamin levels. 1 Publication1
Mutagenesisi212C → A: No effect on cobalamin levels. 1 Publication1
Mutagenesisi226D → A: Decreases methylcobalamin levels, but increases adenosylcobalamin levels. No effect on interaction with MMACHC. 2 Publications1
Mutagenesisi237Y → A: Mildly decreases methylcobalamin levels and strongly increases adenosylcobalamin levels. 1 Publication1
Mutagenesisi266R → A: Mildly decreases methylcobalamin levels and strongly increases adenosylcobalamin levels. 1 Publication1
Mutagenesisi270W → A: Decreases methylcobalamin levels. 1 Publication1
Mutagenesisi278S → A: Marginally decreases methylcobalamin levels and strongly increases adenosylcobalamin levels. 1 Publication1
Mutagenesisi280F → A: No effect on cobalamin levels. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi27249.
MalaCardsiMMADHC.
MIMi277410. phenotype.
OpenTargetsiENSG00000168288.
Orphaneti308380. Methylcobalamin deficiency type cblDv1.
79283. Methylmalonic acidemia with homocystinuria, type cblD.
308442. Vitamin B12-responsive methylmalonic acidemia, type cblDv2.
PharmGKBiPA164723053.

Polymorphism and mutation databases

BioMutaiMMADHC.
DMDMi68565296.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transit peptidei1 – 38MitochondrionSequence analysisAdd BLAST38
ChainiPRO_000001953439 – 296Methylmalonic aciduria and homocystinuria type D protein, mitochondrialAdd BLAST258

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei203N6-acetyllysineCombined sources1

Keywords - PTMi

Acetylation

Proteomic databases

EPDiQ9H3L0.
MaxQBiQ9H3L0.
PaxDbiQ9H3L0.
PeptideAtlasiQ9H3L0.
PRIDEiQ9H3L0.

PTM databases

iPTMnetiQ9H3L0.
PhosphoSitePlusiQ9H3L0.

Expressioni

Tissue specificityi

Widely expressed at high levels.1 Publication

Gene expression databases

BgeeiENSG00000168288.
ExpressionAtlasiQ9H3L0. baseline and differential.
GenevisibleiQ9H3L0. HS.

Organism-specific databases

HPAiHPA037531.
HPA037532.

Interactioni

Subunit structurei

Heterodimer with MMACHC.3 Publications

Protein-protein interaction databases

BioGridi118097. 14 interactors.
IntActiQ9H3L0. 2 interactors.
STRINGi9606.ENSP00000301920.

Structurei

Secondary structure

1296
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi137 – 140Combined sources4
Beta strandi146 – 152Combined sources7
Helixi155 – 162Combined sources8
Beta strandi174 – 181Combined sources8
Helixi191 – 217Combined sources27
Beta strandi222 – 225Combined sources4
Turni227 – 229Combined sources3
Beta strandi231 – 235Combined sources5
Helixi247 – 251Combined sources5
Beta strandi255 – 258Combined sources4
Beta strandi263 – 267Combined sources5
Turni268 – 270Combined sources3
Beta strandi273 – 281Combined sources9
Helixi288 – 293Combined sources6

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5CUZX-ray2.31A108-296[»]
5CV0X-ray1.90A/B108-296[»]
ProteinModelPortaliQ9H3L0.
SMRiQ9H3L0.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiKOG3994. Eukaryota.
ENOG410XRBP. LUCA.
GeneTreeiENSGT00390000015050.
HOGENOMiHOG000231797.
InParanoidiQ9H3L0.
PhylomeDBiQ9H3L0.
TreeFamiTF314208.

Family and domain databases

InterProiIPR019362. MMADHC.
[Graphical view]
PANTHERiPTHR13192. PTHR13192. 1 hit.
PfamiPF10229. MMADHC. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q9H3L0-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MANVLCNRAR LVSYLPGFCS LVKRVVNPKA FSTAGSSGSD ESHVAAAPPD
60 70 80 90 100
ICSRTVWPDE TMGPFGPQDQ RFQLPGNIGF DCHLNGTASQ KKSLVHKTLP
110 120 130 140 150
DVLAEPLSSE RHEFVMAQYV NEFQGNDAPV EQEINSAETY FESARVECAI
160 170 180 190 200
QTCPELLRKD FESLFPEVAN GKLMILTVTQ KTKNDMTVWS EEVEIEREVL
210 220 230 240 250
LEKFINGAKE ICYALRAEGY WADFIDPSSG LAFFGPYTNN TLFETDERYR
260 270 280 290
HLGFSVDDLG CCKVIRHSLW GTHVVVGSIF TNATPDSHIM KKLSGN
Length:296
Mass (Da):32,940
Last modified:July 5, 2005 - v2
Checksum:i749C2A91D7E6C95D
GO

Sequence cautioni

The sequence AAG43124 differs from that shown. Reason: Frameshift at positions 171, 178, 185, 188 and 200.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti204F → S in AAG43124 (Ref. 1) Curated1
Sequence conflicti211I → N in AAG43124 (Ref. 1) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_043843108S → SLAEPLS in MMAHCD; cblD variant 2. 1
Natural variantiVAR_043844182T → N in MMAHCD; cblD variant 1; impairs interaction with MMACHC. 3 PublicationsCorresponds to variant rs118204045dbSNPEnsembl.1
Natural variantiVAR_043845204 – 232Missing in MMAHCD; cblD original. 1 PublicationAdd BLAST29
Natural variantiVAR_043846249Y → C in MMAHCD; cblD variant 1. 1 PublicationCorresponds to variant rs118204046dbSNPEnsembl.1
Natural variantiVAR_043847259L → P in MMAHCD; cblD variant 1; decreases methylcobalamin levels and increases adenosylcobalamin levels; no effect on interaction with MMACHC. 3 PublicationsCorresponds to variant rs118204044dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF060224 mRNA. Translation: AAG43124.1. Frameshift.
AF131802 mRNA. Translation: AAD20048.1.
AF161510 mRNA. Translation: AAF29125.1.
AK313284 mRNA. Translation: BAG36092.1.
AC110782 Genomic DNA. Translation: AAY14891.1.
CH471058 Genomic DNA. Translation: EAX11533.1.
CH471058 Genomic DNA. Translation: EAX11534.1.
CH471058 Genomic DNA. Translation: EAX11535.1.
CH471058 Genomic DNA. Translation: EAX11537.1.
BC000932 mRNA. Translation: AAH00932.1.
BC010894 mRNA. Translation: AAH10894.1.
BC022859 mRNA. Translation: AAH22859.1.
BC023995 mRNA. Translation: AAH23995.1.
CCDSiCCDS2189.1.
RefSeqiNP_056517.1. NM_015702.2.
UniGeneiHs.5324.

Genome annotation databases

EnsembliENST00000303319; ENSP00000301920; ENSG00000168288.
ENST00000428879; ENSP00000389060; ENSG00000168288.
GeneIDi27249.
KEGGihsa:27249.
UCSCiuc002txc.4. human.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF060224 mRNA. Translation: AAG43124.1. Frameshift.
AF131802 mRNA. Translation: AAD20048.1.
AF161510 mRNA. Translation: AAF29125.1.
AK313284 mRNA. Translation: BAG36092.1.
AC110782 Genomic DNA. Translation: AAY14891.1.
CH471058 Genomic DNA. Translation: EAX11533.1.
CH471058 Genomic DNA. Translation: EAX11534.1.
CH471058 Genomic DNA. Translation: EAX11535.1.
CH471058 Genomic DNA. Translation: EAX11537.1.
BC000932 mRNA. Translation: AAH00932.1.
BC010894 mRNA. Translation: AAH10894.1.
BC022859 mRNA. Translation: AAH22859.1.
BC023995 mRNA. Translation: AAH23995.1.
CCDSiCCDS2189.1.
RefSeqiNP_056517.1. NM_015702.2.
UniGeneiHs.5324.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5CUZX-ray2.31A108-296[»]
5CV0X-ray1.90A/B108-296[»]
ProteinModelPortaliQ9H3L0.
SMRiQ9H3L0.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi118097. 14 interactors.
IntActiQ9H3L0. 2 interactors.
STRINGi9606.ENSP00000301920.

PTM databases

iPTMnetiQ9H3L0.
PhosphoSitePlusiQ9H3L0.

Polymorphism and mutation databases

BioMutaiMMADHC.
DMDMi68565296.

Proteomic databases

EPDiQ9H3L0.
MaxQBiQ9H3L0.
PaxDbiQ9H3L0.
PeptideAtlasiQ9H3L0.
PRIDEiQ9H3L0.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000303319; ENSP00000301920; ENSG00000168288.
ENST00000428879; ENSP00000389060; ENSG00000168288.
GeneIDi27249.
KEGGihsa:27249.
UCSCiuc002txc.4. human.

Organism-specific databases

CTDi27249.
DisGeNETi27249.
GeneCardsiMMADHC.
GeneReviewsiMMADHC.
HGNCiHGNC:25221. MMADHC.
HPAiHPA037531.
HPA037532.
MalaCardsiMMADHC.
MIMi277410. phenotype.
611935. gene.
neXtProtiNX_Q9H3L0.
OpenTargetsiENSG00000168288.
Orphaneti308380. Methylcobalamin deficiency type cblDv1.
79283. Methylmalonic acidemia with homocystinuria, type cblD.
308442. Vitamin B12-responsive methylmalonic acidemia, type cblDv2.
PharmGKBiPA164723053.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3994. Eukaryota.
ENOG410XRBP. LUCA.
GeneTreeiENSGT00390000015050.
HOGENOMiHOG000231797.
InParanoidiQ9H3L0.
PhylomeDBiQ9H3L0.
TreeFamiTF314208.

Enzyme and pathway databases

ReactomeiR-HSA-196741. Cobalamin (Cbl, vitamin B12) transport and metabolism.
R-HSA-3359473. Defective MMADHC causes methylmalonic aciduria and homocystinuria type cblD.

Miscellaneous databases

ChiTaRSiMMADHC. human.
GeneWikiiMMADHC.
GenomeRNAii27249.
PROiQ9H3L0.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000168288.
ExpressionAtlasiQ9H3L0. baseline and differential.
GenevisibleiQ9H3L0. HS.

Family and domain databases

InterProiIPR019362. MMADHC.
[Graphical view]
PANTHERiPTHR13192. PTHR13192. 1 hit.
PfamiPF10229. MMADHC. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiMMAD_HUMAN
AccessioniPrimary (citable) accession number: Q9H3L0
Secondary accession number(s): B2R895, D3DP91, O95891
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 5, 2005
Last sequence update: July 5, 2005
Last modified: November 30, 2016
This is version 111 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.